Process for preparing a protected 4-aminomethyl-pyrrolidi-3-one

ABSTRACT

A process for preparing a compound of formula (1) in which P 1  and P 2  are protecting groups; comprising a) reaction of a compound of formula (5) wherein P 1  is as defined for formula (1); with a Raney-nickel catalyst in a solvent under hydrogen to produce a compound of formula (6) wherein P 1  is as defined for formula (1); b) protecting the amino group to produce a compound of formula (7) wherein P 1  and P 2  are as defined for formula (1); and c) selective reduction of the double bond to produce the compound of formula (1).

This application is a 371 of PCT/KR99/00099, Mar. 4, 1999.

TECHNICAL FIELD

The present invention relates to a novel process for preparing aprotected 4-aminomethyl-pyrrolidin-3-one, novel intermediates producedduring this process, and its use in the preparation of quinoloneantibiotics.

BACKGROUND ART

Compounds of formula (1):

in which P¹ and P² are protecting groups are useful as intermediates forpreparing compounds of formula (2).

wherein R is C₁₋₄ alkyl or C₁₋₄ haloalkyl, and salts therof e.g. thedihydrochloride salts;

which are in turn useful as intermediates for preparing quinoloneantibiotics, such as those disclosed in U.S. Pat No. 5,633,262 and EP688772A1. The intermediate of formula (2) in which R is methyl is ofparticular use in the production of the compound(R,S)-7-(3-aminomethyl-4-methoxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and salts thereof, especially(R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate and hydrates thereof including the sesquihydratedisclosed in WO 98/42705.

EP 688772A1 discloses a process for the production of a compound offormula (2) as depicted in Scheme 1:

in Scheme 1 Boc represents t-butoxycarbonyl, and has the same meaningthroughout the present specification.

There are however several drawbacks with the process of scheme 1,particularly if it is to be used on a tens to hundreds of kilogrammescale for commercial production, these include:

a) The process is somewhat inefficient since the use of a reducingagents, such as, platinum under hydrogen atmosphere, palladium metal,lithium aluminum hydride(LAH), lithium borohydride(LiBH₄), sodiumborohydride(NaBH₄), or NaBH₄-trifluoroacetic acid complex, etc., reducesboth the ketone and cyano groups, requiring reoxidation of the alcoholto regenerate the ketone.

b) Reducing agents other than NaBH₄-trifluoroacetic acid complex do notcompletely reduce the cyano group, resulting in the production ofseveral side products and thus a reduction in yield and purity. Althoughthe use of NaBH₄-trifluoroacetic acid complex as a reducing agent mayimprove the yield and purity of the product, its use results in thediscontinuous generation of hydrogen gas. Therefore, explosion riskcannot be adequately prevented by simple exhaust-incineration equipment,and it is not easy to apply this reduction process to production on alarge scale. In addition, since the process for preparing the complexitself has many problems, such as formation of side products, etc., itis inappropriate for use on a large scale.

c) Side reactions which are not observed in small scale production occurmore frequently in a large scale production which leads to a reductionin yield. The undesired side products, some of which are not clearlyidentified, make the separation and/or purification of the desiredproduct difficult. Side products which have been identified include thecompound of formulae (3) and (4):

It is assumed that the side products (3) and (4) are produced byreactions of the starting4-cyano-1-(N-t-butoxy-carbonyl)pyrrolidin-3-one with sodium borohydrideand trifluoroacetic acid. The by-product of formula (3) is particularlytroublesome as it is not easily removed by recrystallization.

d) The pyridine-sulfur trioxide complex used during the oxidation of thehydroxy group is expensive, making it unsuitable for use on anindustrial or commercial scale. In addition, the dimethylsulfide formedas a side product during the oxidation is not environmentallyacceptable.

e) When a transition metal catalyst such as platinum is used inhydrogenation reaction, the reaction does not well proceeded using acatalytic amount of platinum and a low pressure of hydrogen, and thuscannot be used commercially.

Thus, it is desirable to find an alternative process for the productionof the compounds of formulae (1) and (2), particularly one in which anα-cyanoketone derivative can be selectively reduced in such a way thatthe subsequent reoxidation of the hydroxy group is not required.

The present invention is based on the finding that the cyano group of anα-cyanoketone derivative can be selectively reduced to effectivelyproduce the compound of formula (1) using Raney-nickel under hydrogen asreducing agent. The reaction conditions used in this process are verymild and thus can be used for industrial production. The use of aRaney-nickel catalyst gives several advantages over the prior artprocess described above, for example it does not require the additionaloxidation reaction, also, the formation of side products markedlydecreases compared with the process using NaBH₄ as a reducing agent,which leads to a stoichiometric reaction and a good yield.

DISCLOSUE OF THE INVENTION

The present invention provides a process for preparing a compound offormula (1):

in which P¹ and P² are protecting groups; comprising

a) reaction of a compound of formula (5):

wherein P¹ is defined for formula (1); with a Raney-nickel catalyst in asolvent under hydrogen to produce a compound of formula (6):

wherein P¹ is defined for formula (1);

b) protecting the amino group to produce a compound of formula (7):

wherein P¹ and P² are defined for formula (1); and

c) selective reduction of the double bond to produce the compound offormula (1).

The present invention also provides the novel intermediates of formulae(6) and (7).

DETAILED DESCRIPTION OF THE INVENTION

The process of the invention is summarized in Scheme 2:

The above process is more specifically explained hereinafter.

In step a)—reduction of the cyano group, the solvent is preferably analcohol or ether, e.g. methanol or isopropanol, which have been found toimprove the reaction rate. However, suitable solvents are not restrictedto alcohols and ethers, and various inert solvents which do notadversely affect the reaction can be used providing the hydrogenpressure is controlled. The solvent may be used in an amount of 2 to 20times by volume, preferably 2 to 5 times by volume with respect to thecompound of formula (5). The reaction is advantageously conducted in thepresence of one or more additives selected from the group consisting ofammonia water, gaseous ammonia and acetic acid, etc. These additives maybe used in an amount of 2 molar equivalents or more, preferably 2 to 4molar equivalents with respect to the compound of formula (5). The useof these additives has been shown to improve the purity of the resultingcompounds of formula (6).

The step a) reaction is suitably carried out under hydrogen pressuresranging from atmospheric to about 50 atms, preferably from 4 to 10 atms,and suitably at temperatures ranging from room temperature to 60° C.Various types of Raney-nickels can be used as the catalyst in thisreduction reaction, however, Raney-nickel of W-2 type or a similar typethereof is preferably used.

In step b)—protection of the amino group, any suitable amino protectinggroup may be used. The protecting group is preferably removable underacidic conditions. Examples of protecting groups include formyl, acetyl,trifluoroacetyl, benzoyl, para-toluenesulfonyl, methoxycarbonyl,ethoxycarbonyl, t-buthoxycarbonyl, benzyloxycarbonyl,para-methoxybenzyl, trityl, tetrahydropyranyl and pivaloyl. Particularprotecting groups that may be mentioned include acetyl,t-buthoxycarbonyl, and pivaloyl. The preferred protecting group for bothP¹ and P² is t-butoxycarbonyl. Protection of the amino group may beachieved using conditions familiar to those skilled in the art. Forexample by reaction of the compound of formyla (6) with a suitable base,e.g. selected from the group consisting of lithium t-butoxide, lithiumisopropoxide, potassium t-butoxide, sodium t-butoxide, and lithiumchloride, sodium hydroxide and potassium hydroxide. The base is suitablyused in an amount of 2.0 molar equivalents or more, preferably 2.0 to4.0 molar equivalents with respect to the compound of formula (6). Anysolvents conventionally used in organic reactions, such as for example,tetrahydrofuran, toluene, dioxane, dimethoxyethane, etc. may be used,suitably in an amount of 5 to 20 times by volume with respect to thecompound of formula (6). It is desirable to carry out the reaction attemperatures ranging from −40 to 10° C. The reagent for introducing anamino-protecting group may be selected from the group consisting of, forexample, di(t-butoxy)dicarbonate, pivaloyl chloride and acetyl chloride,preferably in an amount of 0.9 to 1.5 molar equivalents with respect tothe compound of formula (6). The resulting compound of formula (7) maybe purified by recrystallization, for example, from a solvent mixture ofalcohol and water e.g. 1:1 to 3:1 by volume.

In step c)—reduction of the double bond, the selective reduction ispreferably carried out using a metal catalyst, e.g. a transition metalcatalyst, such as Raney-nickel, palladium-carbon or Lindlar's catalyst,e.g. in an amount of 0.5 to 20% by weight, preferably 0.5 to 5% byweight with respect to the compound of formula (7), under hydrogen e.g.at a pressure from 1 to 3 atms. It is desirable to maintain the pH ofthe reaction solution at 3 to 5 or 8 to 10 using an organic amine orbuffer solution in order to selectively reduce the double bond at4-position of the pyrrolidine ring without reducing the oxo group at3-position with respect to the hydroxy group. Organic amines which canbe used include tertiary alkylamines such as triethylamine,tri(n-butyl)amine, diisopropylethylamine, etc.; aromatic amines such aspyridine, 4-dimethylaminopyridine, 4-(4-methylpiperidin-1-yl)-pyridine,imidazole, quinoline, isoquinoline, etc.; anilines such asdimethylaniline, etc.; and chiral amines such as triethanolamine,quinine, quinidine, etc. The amine is suitably used in an amount of 0.01to 10 molar equivalents, preferably 1 to 10 molar equivalents withrespect to the starting compound of formula (7). The amines can be usedalone or as mixtures in various ratios. Any conventionally used tertiaryamines in organic reactions can be used for the present reactionalthough they are not specifically listed above.

Any organic solvents, preferably one or more selected from the groupconsisting of alcohols such as methanol, ethanol, n-propanol,isopropanol, etc.; ethers such as tetrahydrofuran, dioxane, etc.;ketones such as acetone, methyl ethyl ketone, etc.; esters such as ethylacetate, butyl acetate, etc. can be used. The auxiliary agents includingthe organic amine, etc. are selected appropriately depending on thesolvent used. The solvent is suitably used in an amount of 5 to 100times by volume, preferably 5 to 20 times by volume with respect to thecompound of formula (7).

When a buffer solution is used instead of the organic amines foradjusting the pH of the reaction solution, only the solvents which donot suddenly precipitate the inorganic salt during the mixing step canbe used, examples of which are tetrahydrofuran, dioxane, acetone,methanol, ethanol, etc. Tetrahydrofuran is most preferred. Solventswhich are not miscible with aqueous solutions, such as ethyl acetate anddiethylether, can also be used in this reaction. Any buffer solutionwhich can adjust the pH of the reaction solution at 3 to 5 or 8 to 10can be used, examples of which are phosphates, acetates, borates, etc.Acetate and borate buffer solution are the most preferred.

The step c) reaction is suitably carried out at temperatures rangingfrom 0 to 50° C., preferably 5 to 40° C.

The compounds of formula (1) produced according to the process of theinvention may be converted to a compound of formula (2) or a saltthereof. Thus according to a further aspect of the invention there isprovided a process for the production of a compound of formula (2):

wherein R is C₁₋₄ alkyl or C₁₋₄ haloalkyl, or a salt therof; whichcomprises reaction of a compound of formula (1), produced by the processof the invention as hereinbefore described, with a compound of formula(8):

R—ONH₂  (8)

wherein R is as defined for formula (2), preferably methyl; followed bydeprotection of the amino groups, and, optionally, salt formation.

The reaction of the compounds of formulae (1) and (8) is preferableconducted in a solvent such as ethyl acetate or tetrahydrofuran. Thedeprotection reaction is preferably conducted under acidic conditions;as the acid, hydrochloric acid gas, sulfuric acid, trifluoroacetic acid,etc. Suitable salts of the compounds of formula (2) include thehydrochloride salts, trifluoroacetate salts or sulfate salts.

The compounds of formula (2) thus prepared according to this furtheraspect of the invention are useful as an intermediates for preparingquinolone antibiotics particularly those described in U.S. Pat. No.5,633,262 and EP 688772A1. Thus according to a further aspect of theinvention there is provided a process for the production of a compoundof formula (9), or a pharmaceutically acceptable salt thereof:

wherein R is as defined for formula (2), which comprises reaction of acompound of formula (2), or a salt thereof, produced by the process ofthe invention as hereinbefore described, with a compound of formula(10):

wherein X is a leaving group, e.g. a halogen atom, preferably chlorine;and optionally forming a pharmaceutically acceptable salt.

The reaction of the compounds of formula (2) and (10) is preferablyconducted in the presence of a base. Further details regarding thereaction of the compounds of formula (2) and (10) can be found in U.S.Pat. No. 5,633,262 and EP 688772A1.

The compound of formula (9) produced according to this aspect of theinvention is preferably(RS)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate or a hydrate thereof, preferably the sesquihydrateas disclosed in WO 98/42705.

The compounds of formulas (6) and (7) which are intermediates in theprocess for preparing the compound of formula (1) are themselves novel.Therefore, the present invention also provides such novel intermediatecompounds.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The present invention will be more specifically explained in thefollowing examples. However, it should be understood that the followingexamples are intended to illustrate the present invention but not in anymanner to limit the scope of the present invention.

COMPARATIVE EXAMPLE 1 Synthesis of4-(N-t-butoxycarbonyl)amino-methyl-1-(N-t-butoxycarbonyl)pyrrolidin-3-ol

3.78 kg(0.1 Kmol) of NaBH₄ and 32 kg of tetrahydrofuran were introducedinto a reactor and the mixture was cooled down to 10° C. or less. 7.0kg(0.034 Kmol) of 4-cyano-1-t-butoxycarbonyl)-pyrrolidin-3-one suspendedin 20 kg of tetrahydrofuran was slowly added thereto. After the additionwas completed, 11.4 kg(0.1 Kmol) of trifluoroacetic acid diluted in 10kg of tetrahydrofuran was added thereto at a temperature of 20° C. orless during which the reaction temperature and generation of hydrogengas were carefully controlled. The reaction solution was stirred forabout 4 hours at room temperature, cooled down to 5° C. or less and thenadjusted to pH 1 to 3 by slowly adding 3N aqueous hydrochloric acidsolution with stirring. Again, the reaction solution was stirred forabout 3 to 4 hours, and 7.63 kg(0.035 Kmol) of di-t-butyldicarbonate wasadded thereto during which the solution was controlled to pH 9 to 10using 25% aqueous sodium hydroxide solution. After the reaction wascompleted, tetrahydrofuran was removed by distillation under reducedpressure. The residue was extracted with ethyl acetate and then driedunder reduced pressure while the solvent was removed. The residue thusobtained was crystallized from 7 l of methyl ethyl ketone and 21 l ofn-hexane and filtered to give 4.74 kg(Yield 45%) of the title compound.

COMPARATIVE EXAMPLE 2 Synthesis of4-(N-t-butoxycarbonyl)amino-methyl-1-(N-t-butoxycarbonyl)-pyrrolidin-3-ol

160 kg(4.23 Kmol) of NaBH₄ and 1000 l of tetrahydrofuran were introducedinto a reactor and the mixture was cooled down to 10° C. or less. 295kg(1.4 Kmol) of 4-cyano-1-(N-t-butoxycarbonyl)-pyrrolidin-3-onesuspended in 1000 l of tetrahydrofuran was slowly added thereto.

After the addition was completed, 479 kg(4.2 Kmol) of trifluoroaceticacid diluted in 800 l of tetrahydrofuran was added thereto at atemperature of 20° C. or less during which the reaction temperature andgeneration of hydrogen gas were carefully controlled. The reactionsolution was stirred for about 4 hours at room temperature, cooled downto 5° C. or less and then adjusted to pH 1 to 3 by slowly adding 3Naqueous hydrochloric acid solution with stirring. Again, the reactionsolution was stirred for about 3 to 4 hours, and 321 kg(1.47 Kmol) ofdi-t-butyldicarbonate was added thereto during which the solution wascontrolled to pH 9 to 10 using 25% aqueous sodium hydroxide solution.After the reaction was completed, tetrahydrofuran was removed bydistillation under reduced pressure. The residue was extracted withethyl acetate and then dried under reduced pressure while the solventwas removed. The residue thus obtained was crystallized from 300 l ofmethyl ethyl ketone and 900 l of n-hexane and filtered to give 131kg(Yield 30%) of the title compound.

EXAMPLE 1 Synthesis of 1-(N-t-butoxycarbonyl)-4-aminomethylenepyrrolidin-3-one(6)

20 kg(95 mol) of 1-(N-t-butoxycarbonyl)-4-cyano-pyrrolidin-3-one wassuspended in 150 l of methanol and then thoroughly dissolved by addingabout 30 l of ammonia water. 100 g of Raney-nickel of type W-2 was addedto the above solution, and the mixture was reacted at room temperatureunder 4 atms of hydrogen pressure. The reaction was completed when theuptake of hydrogen ceased. The catalyst was removed by filtration andsolvent was distilled under reduced pressure to give 20 kg of the titlecompound (quantitative yield).

¹H-NMR(CDCl₃, δ, ppm): 4.95(m, 0.7H), 4.70(m, 0.3H), 4.25(d, 2H),3.90(m, 2H), 1.50(m, 9H); MS (FAB, m/e): 213(M+H); GC(FID) purity:99.8%.

EXAMPLE 2 Synthesis of1-(N-t-butoxycarbonyl)-4-aminomethylene-pyrrolidin-3-one(6)

20 kg(95 mol) of 1-(N-t-butoxycarbonyl)-4-cyano-pyrrolidin-3-one wassuspended in 150l of tetrahydrofurane. 100 g of Raney-nickel of type W-2was added to the above solution, and the mixture was reacted at roomtemperature under 4 atms of hydrogen pressure. The reaction wascompleted when the uptake of hydrogen ceased. The catalyst was removedby filtration and solvent was distilled under reduced pressure to give20 kg of the title compound (quantitative yield).

EXAMPLE 3 Synthesis of1-(N-t-butoxycarbonyl)-4-aminomethylene-pyrrolidin-3-one(6)

20 kg(95 mol) of 1-(N-t-butoxycarbonyl)-4-cyano-pyrrolidin-3-one wassuspended in 150l of isopropanol. 100 g of Raney-nickel of type W-2 wasadded to the above solution, and the mixture was reacted at roomtemperature under 4 atms of hydrogen pressure. The reaction wascompleted when the uptake of hydrogen ceased. The catalyst was removedby filtration and solvent was distilled under reduced pressure to give20 kg of the title compound (quantitative yield).

EXAMPLE 4 Synthesis of1-(N-t-butoxycarbonyl)-4-(t-butoxycarbonyl)aminomethylenepyrrolidin-3-one(7)

500 g(2.36 mol) of1-(N-t-butoxycarbonyl)-4-aminomethylene-pyrrolidin-3-one prepared inExample 1 was suspended in 5 l of toluene and the resulting suspensionwas cooled down to −20° C. 380 g(4.72 mol) of lithium-t-butoxide wasadded thereto while the temperature was maintained to −10° C. or less.570 g(2.6 mol) of di-t-butyldicarbonate dissolved in 500 ml oftetrahydrofuran was added to the above solution at

−1° C. or less to complete the reaction. This solution was neutralizedby 1N hydrochloric acid solution and the aqueous layer was discarded.The organic layer was washed with aqueous sodium chloride solution, anddistilled under reduced pressure. The residue was recrystallized from asolvent mixture of ethanol and water (2/1, v/v) to give 650 g (Yield90%) of the title compound.

¹H NMR(CDCl₃, δ, ppm): 10.10(s, 1H), 7.30(s, 1H), 4.40(d, 2H), 3.95(d,2H), 1.55(m, 18H); MS(FAB, m/e):313(M+H); HPLC purity: 98.0%.

EXAMPLE 5 Synthesis of1-(N-t-butoxycarbonyl)-4-(t-butoxycarbonyl)aminomethylenepyrrolidin-3one(7)

500 g(2.36 mol) of1-(N-t-butoxycarbonyl)-4-aminomethylene-pyrrolidin-3-one prepared inExample 2 was suspended in 5 l of tetrahydrofurane and the resultingsuspension was cooled down to −20° C. 570 g(2.6 mol) ofdi-t-butyldicarbonate dissolved in 500 ml of tetrahydrofuran was addedto the above solution at 0° C. or less. 380 g of sodium hydroxide inwater (700 ml) was added thereto while the temperature was maintained to0° C. or less to complete the reaction. This solution was neutralized by1N hydrochloric acid solution and the aqueous layer was discarded. Theorganic layer was washed with aqueous sodium chloride solution, anddistilled under reduced pressure. The residue was recrystallized from asolvent mixture of ethanol and water (2/1, v/v) to give 650 g (Yield90%) of the title compound.

EXAMPLE 6 Synthesis of1-(N-t-butoxycarbonyl)-4-(t-butoxycarbonyl)aminomethylenepyrrolidin-3-one(7)

500 g(2.36 mol) of 1-(N-t-butoxycarbonyl)-4-aminomethylene-pyrrolidin-3-one prepared in Example 3 was suspended in 5 l ofisopropanol and the resulting suspension was cooled down to −20° C. 570g(2.6 mol) of di-t-butyldicarbonate dissolved in 500 ml of isopropanolwas added to the above solution at 0° C. or less. 380 g of sodiumhydroxide in water (700 ml) was added thereto while the temperature wasmaintained to 0° C. or less to complete the reaction. This solution wasneutralized by 1N hydrochloric acid solution and the aqueous layer wasdiscarded. The organic layer was washed with aqueous sodium chloridesolution, and distilled under reduced pressure. The residue wasrecrystallized from a solvent mixture of ethanol and water (2/1, v/v) togive 650 g (Yield 90%) of the title compound.

EXAMPLE 7 Synthesis of1-(N-t-butoxycarbonyl)-4-(t-butoxycarbonyl)aminomethylpyrrolidin-3-one(1)

500 mg(1.6 mmol) of1-(N-t-butoxycarbonyl)-4-(t-butoxycarbonyl)aminomethylenepyrrolidin-3-one(7)prepared in Example 2 was dissolved in 10 ml of n-propanol, and 1.2ml(4.8 mmol) of tri-n-butylamine was added thereto. 20 g of palladiumcatalyst was added to the above solution and then the mixture wasreacted for 24 hours at room temperature under 1 atm of hydrogenpressure. The palladium catalyst was removed by filtration, and thefiltrate was diluted with 30 ml of ethyl acetate. The resulting solutionwas washed with 1N hydrochloric acid solution, washed again with aqueoussodium chloride solution, and then distilled under reduced pressure togive 480 mg of the title compound quantitatively.

¹H-NMR(CDCl₃, δ, ppm): 4.95(s, 1H), 4.05(t, 1H), 3.95(s, 1H), 3.63(d,1H), 3.32(m, 1H), 3.34(m, 2H), 2.76(m, 1H), 1.44(m, 18H);MS(FAB):315(M+H); HPLC purity: 97.2%.

EXAMPLE 8 Synthesis of1-(N-t-butoxycarbonyl)-4-(t-butoxycarbonyl)aminomethylpyrrolidin-3-one(1)

500 g(1.6 mol) of1-(N-t-butoxycarbonyl)4-(t-butoxycarbonyl)aminomethylenepyrrolidin-3-one(7)prepared in Example 2 was dissolved in 5 l of tetrahydrofuran, and 500ml of borate buffer solution(pH=9.0 ±1) was added thereto. 20 g ofpalladium catalyst was added to the above solution and then the mixturewas reacted for 6 hours at room temperature under 1 atm of hydrogenpressure. The palladium catalyst was removed by filtration, thetetrahydrofuran was distilled under reduced pressure, and the residuewas diluted with 500 ml of ethyl acetate. The resulting solution wassequentially washed with 1N hydrochloric acid solution, saturatedaqueous sodium bicarbonate solution and aqueous sodium chloridesolution. Then, the organic layer was distilled under reduced pressureto give 500 g of the title compound quantitatively.

REFERENCE EXAMPLE 1 Synthesis of3-aminomethyl-4-methoxyimino-pyrrolidine hydrochloride(2)

30 g(0.09 mol) of 1 -(N-t-butoxycarbonyl)4-(t-butoxycarbonyl)aminomethylpyrrolidin-3-one(l) prepared in Example 3 was dissolved in 150 mlof ethyl acetate. 9.06 g(0.11 mol) of methoxylamine was added thereto atroom temperature and the resulting solution was cooled down to 0° C., towhich was added dropwise 4.3 g(0.11 mol) of sodium hydroxide dissolvedin 17 ml of water in a cold state. 5 ml of acetic acid was addeddropwise thereto and the resulting solution was stirred for about3 hoursat room temperature. After layer formation, the aqueous layer wasdiscarded, and the organic layer was washed once with saturated salineand then distilled under reduced pressure to give a yellow liquid. 120ml of methanol was added to the liquid and the resulting solution wascooled down to 0° C. 21.2 g(0.27 mol) of acetyl chloride was slowlyadded dropwise to the cooled solution, which was then warned to roomtemperature, stirred for about 3 hours and filtered. The white crystalthus obtained was washed with 40 ml of ethyl acetate to give 15.6g(Yield 80%) of the title compound,

REFERENCE EXAMPLE 2 Synthesis of7-(3-aminomethyl-4-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro[1,8]-naphthyridine-carboxylicacid (9)

141 mg (0.5 mmole) of1-cyclopropyl-7-chloro-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylicacid and 108 mg (0.5 mmole) of 3-aminomethylpyrrolidin-4-oneO-methyloxime dihydrochloride were added to 2.5 ml of dry acetonitrile.Then, 230 mg (1.5 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene was slowlyadded dropwise thereto and the mixture was heated for 0.5 hour and thencooled down to room temperature. 1 ml of distilled water was added tothe reaction solution. The precipitated solid was separated and dried toobtain 167 mg (Yield: 85%) of the title compound.

What is claimed is:
 1. A process for preparing a compound of formula(1):

in which P¹ and P² are protecting groups; comprising a) reaction of acompound of formula (5):

 wherein P¹ is as defined for formula (1); with a Raney-nickel catalystin a solvent under hydrogen to produce a compound of formula (6):

 wherein P₁ is as defined for formula (1); b) protecting the amino groupto produce a compound of formula (7):

 wherein P¹ and P² are as defined for formula (1); and c) selectivereduction of the double bond to produce the compound of formula (1). 2.The process according to claim 1, wherein P¹ and P² are independentlyselected from acetyl, t-butoxycarbonyl and pivaloyl.
 3. The processaccording to claim 2, wherein P¹ and P² are both t-butoxycarbonyl. 4.The process according to claim 1, wherein the solvent in step a) is analcohol or an ether.
 5. The process according to claim 1, wherein instep a) the solvent is used in an amount of 2 to 20 times by volume withrespect to the compound of formula (5), the hydrogen pressure is fromatmospheric pressure to 50 atms, and the reaction temperature is fromroom temperature to 60° C.
 6. The process according to claim 1, whereinthe Raney-nickel catalyst in step a) is type W-2.
 7. The processaccording to claim 1, wherein one or more additives selected from thegroup consisting of ammonia water, gaseous ammonia and acetic acid isused in an amount of 2 to 4 molar equivalents with respect to thecompound of formula (5) in step a).
 8. The process according to claim 1,wherein the compound of formula (6) is reacted withdi(t-butoxy)dicarbonate, pivaloyl chloride or acetyl chloride in stepb).
 9. The process according to claim 1, wherein one or more basesselected from the group consisting of lithium t-butoxide, lithiumisopropoxide, potassium t-butoxide, sodium t-butoxide, lithium chloride,sodium hydroxide and potassium hydroxide are used in an amount of 2.0 to4.0 molar equivalents with respect to the compound of formula (6), oneor more solvents selected from the group consisting of tetrahydrofuran,toluene and dioxane are used in an amount of 5 to 20 times by volumewith respect to the compound of formula (6), and the temperature rangesfrom −40 to 10° C. in step b).
 10. The process according to claim 1,wherein the compound of formula (7) prepared in step b) isrecrystallized in a solvent mixture of ether or alcohol and water in avolume ratio of 1:1 to 3:1 prior to its use in step c).
 11. The processaccording to claim 1, wherein one or more metal catalysts selected fromthe group consisting of Raney-nickel, palladium-carbon and Lindlar'scatalyst are used in an amount of 0.5 to 20% by weight with respect tothe compound of formula (7), one or more solvents selected from thegroup consisting of methanol, ethanol, n-propanol, isopropanol,tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetateand butyl acetate are used in an amount of 5 to 100 times by volume withrespect to the compound of formula (7), and the reaction temperatureranges from 0 to 50° C. in step c).
 12. The process according to claim2, wherein in step c) the pH of the reaction solution is adjusted to 8to 10 using one or more organic amines selected from the groupconsisting of triethylamine, tri(n-butyl)amine, diisopropylethylamine,pyridine, 4-dimethylaminopyridine, 4-(4-methyl-piperidin-1-yl)-pyridine,imidazole, quinoline, isoquinoline, dimethylaniline, triethanolamine,quinine and quinidine in an amount of 0.01 to 10 molar equivalents withrespect to the compound of formula (7), or to 3 to 5 or 8 to 10 usingone or more buffer solutions selected from the group consisting ofphosphates, acetates and borates.
 13. A compound of formula (6):

in which P¹ represents a protecting group.
 14. A compound according toclaim 13, wherein P₁ is acetyl, t-butoxycarbonyl or pivaloyl.
 15. Acompound of formula (7):

in which P¹ and P² represent protecting groups.
 16. A compound accordingto claim 14, wherein P¹ and P² independently represent acetyl,t-butoxycarbonyl or pivaloyl.
 17. A process for the production of acompound of formula (2):

wherein R is C₁₋₄ alkyl or C₁₋₄ haloalkyl, or a salt thereof whichcomprises reaction of a compound of formula (1), produced according toclaim 1, with a compound of formula (8): R—ONH₂  (8) wherein R is asdefined for formula (2); followed by deprotection of the amino groups,and, optionally, salt formation.
 18. The process according to claim 17,wherein the compound of formula (2) is3-aminomethyl-4-methoxyiminopyrrolidine hydrochloride.
 19. A process forthe production of a compound of formula (9), or a pharmaceuticallyacceptable salt thereof:

wherein R is as defined for formula (2) in claim 17, which comprisesreaction of a compound of formula (2), or a salt thereof, producedaccording to the process of claim 17, with a compound of formula (10):

wherein X is a leaving group; and optionally forming a pharmaceuticallyacceptable salt.
 20. The process of claim 14, wherein the compound offormula (9) is(R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid or a pharmaceutically acceptable salt thereof.
 21. The process ofclaim 20, wherein the compound of formula (9) is(R,S)-7-(3-aminomethyl-4-syn-methoxyimino-pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylicacid methanesulfonate sesquihydrate.